Consensus-defined sarcopenia predicts adverse outcomes after elective abdominal surgery: meta-analysis

Abstract Background Sarcopenia refers to the progressive age- or pathology-associated loss of skeletal muscle. When measured radiologically as reduced muscle mass, sarcopenia has been shown to independently predict morbidity and mortality after elective abdominal surgery. However, the European Working Group on Sarcopenia in Older People (EWGSOP) recently updated their sarcopenia definition, emphasizing both low muscle ‘strength’ and ‘mass’. The aim of this systematic review and meta-analysis was to determine the prognostic impact of this updated consensus definition of sarcopenia after elective abdominal surgery. Methods MEDLINE, Embase, Scopus, and Cochrane Central Register of Controlled Trials (CENTRAL) databases were systematically searched for studies comparing prognostic outcomes between sarcopenic versus non-sarcopenic adults after elective abdominal surgery from inception to 15 June 2022. The primary outcomes were postoperative morbidity and mortality. Sensitivity analyses adjusting for confounding patient factors were also performed. Methodological quality assessment of studies was performed independently by two authors using the QUality in Prognosis Studies (QUIPS) tool. Results Twenty articles with 5421 patients (1059 sarcopenic and 4362 non-sarcopenic) were included. Sarcopenic patients were at significantly greater risk of incurring postoperative complications, despite adjusted multivariate analysis (adjusted OR 1.56, 95 per cent c.i. 1.39 to 1.76). Sarcopenic patients also had significantly higher rates of in-hospital (OR 7.62, 95 per cent c.i. 2.86 to 20.34), 30-day (OR 3.84, 95 per cent c.i. 1.27 to 11.64), and 90-day (OR 3.73, 95 per cent c.i. 1.19 to 11.70) mortality. Sarcopenia was an independent risk factor for poorer overall survival in multivariate Cox regression analysis (adjusted HR 1.28, 95 per cent c.i. 1.13 to 1.44). Conclusion Consensus-defined sarcopenia provides important prognostic information after elective abdominal surgery and can be appropriately measured in the preoperative setting. Development of targeted exercise-based interventions that minimize sarcopenia may improve outcomes for patients who are undergoing elective abdominal surgery.


Introduction
Sarcopenia refers to the generalized and often progressive loss of skeletal muscle mass that is primarily caused by ageing, but may also result from malnutrition, malignancy, or other underlying disease pathophysiology [1][2][3] . The European Working Group on Sarcopenia in Older People (EWGSOP) has defined sarcopenia as 'muscle failure' occurring secondary to muscle changes that accrue across a lifetime 4 . Sarcopenia is increasingly being recognized as a risk factor for complications after major gastrointestinal surgery 5 , over and above age, cancer diagnosis, and measures of nutritional status.
When measured as reduced skeletal muscle mass by CT, sarcopenia has recently been identified as a poor prognostic indicator in patients after major oncological and elective abdominal surgery 6,7 . The EWGSOP initially proposed that sarcopenia should be measured as reduced skeletal muscle 'mass' on its own due to its prognostic significance in the context of elective abdominal surgery 8 . Skeletal muscle mass is assessed using a wide range of imaging modalities, including CT, bioelectrical impedance analysis (BIA), dual-energy X-ray absorptiometry (DEXA), and ultrasonography 9 . Traditionally, cut-off values and references used to define sarcopenia have been heterogeneous, limiting its clinical utility 10 .
In 2019, however, the consensus definition was further updated to focus on reduced muscle 'function', measured as low muscle 'strength' and/or 'performance', together with objective radiological evidence of low muscle quantity or quality used to confirm a sarcopenia diagnosis 4 . Handgrip strength (HGS) is a universal metric with standardized cut-offs defined by the EWGSOP (based on European populations) and the Asian Working Group for Sarcopenia (AWGS) (based on Asian populations), which has been correlated with muscle 'strength' 1,11 . In addition, gait speed (GS) has also been suggested as a measure of muscle 'performance' by these groups 1,11 . The addition of these standardized metrics to skeletal muscle mass may provide a more accurate method for determining the presence of sarcopenia 10 . However, the prognostic impact of this new method of measuring sarcopenia, in patients undergoing elective abdominal surgery, remains to be determined. This knowledge would aid in educating patients about their likely postoperative course, together with obtaining informed consent, and in developing targeted interventions to minimize sarcopenia for these patients 12,13 .
The hypothesis is that, compared with non-sarcopenic adults, those with sarcopenia would have lower physiological reserves and hence are likely to be at higher risk of incurring postoperative complications and mortality in both the short and long term after any elective abdominal procedure. Therefore, the aim of this systematic review and meta-analysis was to determine the prognostic impact of sarcopenia, when defined according to the EWGSOP, after elective abdominal surgery.

Methods
The protocol for this study was registered on PROSPERO (CRD42 022337609) 14 and was reported according to the PRISMA 15 and Meta-analysis Of Observational Studies in Epidemiology (MOOSE) 16 guidelines (Appendix S1).

Information sources
The MEDLINE (Ovid), Embase (Ovid), Scopus, and Cochrane Central Register of Controlled Trials (CENTRAL) electronic databases were systematically searched for studies published between database inception and 15 June 2022. Bibliography lists for all included studies and systematic reviews on relevant topics were also manually screened to ensure all potentially eligible studies were identified.

Search strategy
The following keywords and Medical Subject Headings (MeSH) were combined using Boolean operators ('AND'/'OR'), proximity search terms ('adj3'), and the 'explode' function where possible: 'physical examination', 'clinical marker', 'muscle atrophy', 'musc* wast*', 'sarcopen*', 'laparotomy', 'digestive system surgical procedures', 'colorectal surgery', 'general surgery', 'abdom* surgery', and 'abdom* operation'. Appendix S2 demonstrates the search string applied in the MEDLINE (Ovid) database. Searches were restricted to studies conducted in adult populations (greater than or equal to 18 years old) that were published in English and where the full text was accessible. There were no limitations on study design or geographical location.

Study selection
All original studies assessing the outcomes of sarcopenic compared with non-sarcopenic adults after elective abdominal surgery were included in the present review. Sarcopenia was defined in accordance with the EWGSOP, as either reduced skeletal muscle 'mass' together with reduced muscle function ('strength' and/or 'performance') (definition one) or reduced skeletal muscle 'strength' and reduced muscle 'quantity' or 'quality' (definition two). Any imaging modality used to measure skeletal muscle quantity and quality (including CT, BIA, and ultrasonography), strength (hand dynamometer), and performance (GS test, short physical performance battery test, and the Timed 'Up and Go' test) was considered. In cases where studies included an identical cohort of patients originating from the same institution and across overlapping intervals of time, only the study published most recently was included.
Studies that did not use either of the EWGSOP definitions for sarcopenia were excluded, as were editorial letters, systematic and/or literature reviews, case reports or small case series (with fewer than 10 patients), studies including paediatric patients (aged less than 18 years old), and conference abstracts (where the full text could not be sourced).

Screening process
Records were exported into EndNote X9 (Clarivate, Philadelphia, PA, USA), with duplicates being excluded via the methods of Bramer et al. 17 . Two reviewers screened these records independently using the Rayyan web application for systematic reviews 18 . Consensus was necessary before study inclusion, with discrepancies being resolved via senior author input as required.

Data extraction
Study characteristics, operative details, patient selection criteria, sarcopenia definitions, patient characteristics, and postoperative morbidity and mortality outcomes were extracted (Table S1). Data presented as figures and/or graphs were extracted using WebPlotDigitizer (Version 4.5; Pacifica, CA, USA) 19 . Data were validated by a second author independently, with any disagreements mediated by a senior author. In cases where included studies adjusted for potentially confounding patient factors through multivariate analysis, the adjusted OR (aOR), adjusted HR (aHR), 95 per cent confidence interval (c.i.), and covariates included within each model were also extracted when reported.

Quality assessment
Methodological quality assessment of studies was performed independently by two authors using the QUality in Prognosis Studies (QUIPS) tool 20 . Final agreement on scores was achieved through discussion, including input from a senior author if required.

Outcome measures
The primary endpoints of this study were postoperative morbidity and mortality. Morbidity was defined according to the Clavien-Dindo (CD) classification scale 21 and analysed as rates of overall (greater than or equal to one CD grade I-V), major (greater than or equal to one CD grade III-V), and moderate-to-minor (greater than or equal to one CD grade I-II) complications, separately. Mortality was measured during the index hospital stay (in hospital) and in the short term (at 30-and 90-day follow-up). Secondary endpoints included postoperative and total length of stay (LOS), unplanned hospital readmissions and reoperations, and long-term mortality (6 months, 1 year, and 2 years after surgery).

Meta-analysis
Categorical and continuous data from the univariate (unadjusted) analysis in each study were reported as the frequency (n) and mean(s.d.) respectively. When the s.d. was not reported, it was imputed from available data using validated methods 23,24 . Continuous data reported as the median and range (or interquartile range) were converted to the mean and s.d. for the purposes of this analysis 25,26 . Continuity corrections were applied to categorical data with zero frequencies, by adding one to both the numerator and denominator 27 . Summary estimates were reported as pooled OR and mean differences (MD) for categorical and continuous endpoints respectively (with their 95 per cent c.i.). Sarcopenia prevalence and incidence rates for overall postoperative complications and in-hospital mortality were reported as the pooled prevalence and incidence (percentage) (also with their associated 95 per cent c.i.). HRs derived from Cox proportional-hazards regression models in studies reporting on overall survival were analysed where possible. Statistically significant differences were denoted by 95 per cent c.i. that did not cross the no effect line (zero for continuous endpoints and one for categorical endpoints). A random-effects meta-analysis with the DerSimonian-Laird estimator was used for all analyses to minimize the impact of the expected variability in patient demographic characteristics and sarcopenia cut-off values between studies 28 . Heterogeneity between studies for each outcome was quantified with the I 2 statistic 29 , with cut-off values of 0-29, 30-49, 50-74, and 75-100 per cent being used to denote studies as being not significantly heterogeneous, moderately heterogeneous, substantially heterogeneous, and considerably heterogeneous respectively. Publication bias was assessed quantitatively using Peter's or Egger's regression test for categorical and continuous endpoints respectively 30,31 . P values of <0.050 were indicative of publication bias.

Subgroup and sensitivity meta-analyses
Subgroup meta-analyses were conducted based on the type of resection (gastric versus oesophageal versus colorectal versus liver transplantation). Sensitivity analysis of studies that performed multivariate regression analyses for any of the outcomes was also performed. The generic inverse-variance meta-analysis method was used to assign weighting to each study in this analysis 32 , with results reported as pooled aOR or aHR (with their respective 95 per cent c.i.).

Study selection
The initial search of databases identified 2816 records, from which 24 studies were considered for inclusion  . Seven of these studies reported on identical patient cohorts and hence only the most recent of these studies, by Chen et al. 37 , Lou et al. 44 , and Makiura et al. 45 , were included. After exclusion of the duplicate reports 53-56 , a total of 20 studies were analysed in the present review ( Fig. 1).

Study characteristics
The characteristics of each study are presented in Table 1.
Gastrectomy accounted for the majority of operations (10 studies), followed by liver transplantation (3 studies), colorectal resection and oesophagectomy (2 studies each), gynaecological operations (1 study), 'gastrointestinal cancer surgery' (1 study), and pancreatoduodenectomy (1 study). Elective operations were indicated for cancer in all studies aside from two 41,42 , in which liver transplantation was performed for a variety of benign and malignant indications.

Quality assessment
Results of the quality assessment using the QUIPS tool are displayed in Table S2. Of the 20 included studies, 15 (75.0 per cent) were scored as being at low risk of bias for each of the domains. Şengül Ayçiçek et al. 34 did not adjust for potentially confounding covariates in their analyses and their study population was not representative of the population of interest, resulting in a high risk of bias for each of the respective bias domains. A high risk of attrition bias was also observed in Welch et al. 49 due to a large percentage of patients who declined to participate in the study by 1-week follow-up (28.6 per cent, two of seven patients).

Sarcopenia definitions
All studies measured both skeletal muscle mass (as the skeletal muscle index (SMI)) and muscle strength (as the HGS) ( Table 2).
A total of seven studies utilized definition one for sarcopenia, whereas definition two was applied in 11 studies; the definition used was not specified in two studies 42,47 . Şengül Ayçiçek et al. 34 further categorized some patients as having 'severe' sarcopenia, characterized by low muscle 'strength', 'mass', and 'performance'. Skeletal muscle mass was measured with cross-sectional abdominal CT at the level of L3 in most studies (12 studies). Cut-off values for reduced muscle mass were heterogeneous across studies and were also not sex specific.
Other modalities used to measure skeletal muscle mass included BIA (six studies), ultrasonography (one study), DEXA (one study), and both BIA and ultrasonography (one study). In addition, muscle quality was measured by the mean skeletal muscle attenuation (SMA; in Hounsfield units) in two studies [50][51] .
The sarcopenia definition and cut-off established by Zhuang et al. 57 were used in four studies. An electronic hand-held dynamometer was used to evaluate muscle strength (in kg) in most studies (17 studies), with the remainder not stating the tool that was used. Sex-specific values of less than 26 kg in men and less than 18 kg in women (11 studies) [36][37][38]41,42,44,45,[50][51][52][53] and less than 27 kg in men and less than 16 kg in women (4 studies) 33,34,39,43 were the most frequently used thresholds to indicate low muscle strength. Muscle performance was estimated using either the GS (14 studies) or the Timed 'Up and Go' test (1 study) 48 . The cut-off for low skeletal muscle performance was 0.8 m/s across all studies in which GS was reported, consistent with definitions established by the EWGSOP and AWGS 4,11 . Most studies stated that sarcopenia assessment using the EWGSOP definition was relatively 'easy' to conduct and would be suitable for practical application in the elective setting.

Patient characteristics
Elective abdominal surgery was performed in a total of 5421 patients. Patient demographic and preoperative characteristics are outlined in

Primary endpoints
The incidence of overall morbidity after elective abdominal surgery was 29 per cent (95 per cent c.i. 20 to 44 per cent; I 2 = 99 per cent; Fig. S1a Fig. 3a). There was no heterogeneity between the analysed studies (I 2 = 0 per cent). Multivariate Cox regression analyses revealed sarcopenia as an independent risk factor for poorer overall survival (aHR 1.

Secondary endpoints
Results of the meta-analyses for secondary endpoints are displayed in Table 3 48 after surgery was higher in sarcopenic compared with non-sarcopenic patients, although these outcomes were reported in only one study each. Significantly higher unplanned readmissions at 90-day follow-up were also demonstrated among sarcopenic patients in multivariate regression analysis in one study (aOR 3.71, 95 per cent c.i. 1.29 to 11.05) 45 .

Publication bias
Publication bias was not evident for overall morbidity (P = 0.15) and major complications (P = 0.34). The remainder of primary and secondary endpoints were infrequently reported and hence publication bias could not be determined for these outcomes.

Subgroup meta-analyses
Pancreatoduodenectomy and gynaecological procedures were analysed in one study each and thus separate subgroup meta-analyses could not be performed for these operations due to the insufficient number of studies.

Gastric
Congruent with the overall analysis, sarcopenic patients undergoing gastric surgery were significantly more likely to incur any postoperative morbidity (

Colorectal
Chen et al. 37 showed that sarcopenic patients have higher rates of overall postoperative morbidity (OR 2.22, 95 per cent c.i. 1.35 to 3.66) after colorectal resections. Rates of unplanned readmissions and total hospital LOS did not differ between sarcopenic and non-sarcopenic cohorts (Table S6).

Liver transplantation
Outcomes among sarcopenic patients undergoing liver transplantation were similar to those of the overall analysis (

Sensitivity analysis
Multivariate regression analyses were performed in all but three studies 36,44,51 . These studies adjusted for a range of potentially confounding preoperative and patient demographic factors (refer to Table S8 for the list of included covariates).

Discussion
This systematic review and meta-analysis has shown that sarcopenia, when defined using low muscle mass and function (strength and/or performance) according to the EWGSOP, provides    important prognostic information after elective abdominal surgery. Sarcopenic patients were at consistently greater risk of incurring postoperative complications, regardless of type of elective operation and despite adjustment for confounding preoperative and patient factors. Furthermore, postoperative mortality rates were consistently higher among sarcopenic patients up to 1-year follow-up, with sarcopenia identified as an independent risk factor for poorer overall survival after elective abdominal surgery.
Current consensus statements do not recommend the use of muscle mass on its own to define sarcopenia because of a non-linear relationship between muscle mass and function 4,10,11 . Muscle mass is measured using different modalities, such as axial CT, BIA, ultrasonography, and/or DEXA, some of which require specialized training and thus may be more costly and less straightforward to interpret. Furthermore, the lack of standardized cut-off values for the SMI,  which is the most frequently used metric to quantify muscle mass, has hindered its clinical utility 4 . Standardization of measures and cut-offs for skeletal muscle mass may be the key in achieving translation of the revised EWGSOP definitions for sarcopenia into routine clinical practice. The updated EWGSOP guidelines place an increased emphasis on muscle 'strength' in sarcopenia diagnosis, with recognition that strength may be better than mass at predicting adverse outcomes 4 . Consistent with the updated proposal made by the EWGSOP, the combination of these measures may provide the most accurate assessment of sarcopenia 10 . Several studies in the present review have highlighted that sarcopenia, when defined according to the EWGSOP, is relatively simple to assess in the clinic setting before an elective abdominal operation [35][36][37]41,43,47,50 . Measures of muscle strength and performance, such as HGS and GS, are inexpensive and may be determined non-invasively using an electronic hand-held dynamometer and simple timed gait test respectively. Additionally, the development of standardized cut-off values for HGS and GS by consensus groups, such as the EWGSOP and AWGS, have facilitated the interpretation of muscle strength and performance 4,11 .
Given the high preoperative prevalence of sarcopenia of 20 per cent among patients undergoing elective abdominal surgery, early recognition and treatment of sarcopenia may allow for optimization of postoperative outcomes 12 . Simple exercise interventions have consistently been shown to result in significant improvements to muscle strength, muscle mass, and muscle performance, such as in the timing of sit-to-stand and walking speed tests in a recent review 13 . Compared with preoperative/prehabilitation interventions, those commenced in the early postoperative interval (within 6 weeks after surgery) led to greater improvements in muscle mass and GS, whilst late postoperative interventions (more than 6 weeks after surgery) were more effective at reducing timed gait test scores 13 . Structured exercise-based programmes are increasingly being advocated for as part of enhanced recovery protocols (ERPs) for patients undergoing major non-cardiac surgery 58 59 demonstrated a trend toward improvements in GS and other timed tests in patients who have trialled prehabilitation exercises before undergoing elective colorectal surgery. However, 42 per cent of patients were excluded as they could not participate in such interventions due to extremely short elective surgery wait times (of less than 2 weeks). It is also anticipated that patient compliance may be higher with the introduction of postoperative rather than preoperative/ prehabilitation exercise-based regimens in the context of elective surgery, given the interval of postoperative monitoring required after surgery. Furthermore, in cachectic patients with cancer, such prehabilitation exercise-based interventions may be counteracted by the cancer pathophysiology itself, which suggests that postoperative interventions may show greater efficacy in improving sarcopenia for these patients. Therefore, the utility of postoperative exercise interventions when incorporated into ERPs, particularly in the interval immediately after surgery, needs to be further assessed for their potential to improve outcomes for sarcopenic patients after elective abdominal surgery. Elective abdominal surgery was indicated for cancer in all but two studies 41,42 . Cancer patients may have reduced physiological reserves secondary to their underlying disease pathophysiology, such as cancer-related cachexia and malnutrition 3 . This may result in a diminished ability to respond to the stress response initiated by the 'surgical insult', making these patients more vulnerable to adverse perioperative and postoperative outcomes 3 . In turn, major abdominal surgery is known to cause persistent inflammation and immunosuppression through the release of pro-inflammatory cytokines, which results in risk of prolonged critical illness and mortality 60 . Such risk is compounded in sarcopenic patients who already have decreased physiological and homeostatic reserves. Failure to recognize the higher needs of these sarcopenic patients may translate into inadequate patient-centred planning, increased hospital costs, and incidence of 'failure to rescue', which refers to the inability of the health service to prevent death after the development of a postoperative complication 61 . Early diagnosis of sarcopenia ensures that patient-centred bundles of care, comprising supplemental nutrition, exercise-based interventions, shared care with geriatric and medical services, and early recognition and management of postoperative complications, are instituted at an earlier stage to optimize outcomes for sarcopenic patients with cancer after elective abdominal surgery 61 .
Included studies were most commonly conducted in Eastern Asia (eight studies in Japan and seven studies in China). Whilst this may have contributed to the low heterogeneity observed between studies, the prevalence of sarcopenia is known to vary based on ethnicity and race 62 , signifying that the results may not be generalizable to patient populations outside of these geographical regions. In addition, cut-off values for the sarcopenic parameters of SMI, HGS, and GS were originally defined in European populations by the EWGSOP and thus may be less applicable to patients who are from varying ethnic and/or racial backgrounds. Therefore, further work is required to establish optimal cut-off thresholds for sarcopenic parameters and whether sarcopenia may have equivalent prognostic implications after elective abdominal surgery in ethnically and racially diverse patient populations. This review has several limitations. There was a wide degree of variability in modalities and parameters used to quantify muscle mass, strength, and performance between studies, as well as in the cut-off values used to define sarcopenia. In addition, elective abdominal operations consisted of a range of different procedures, likely with differing risk profiles. Nonetheless, a random-effects model was used for all meta-analyses, together with subgroup analyses stratified by the type of resection (gastric versus oesophageal versus colorectal versus liver transplantation). Results of the subgroup analyses did not differ from the overall analysis, suggesting that variations in the type of operation performed are unlikely to have contributed to the observed heterogeneity. Despite this, heterogeneity between the studies was low and not considered statistically significant for most endpoints. Lastly, several studies reported on identical patient cohorts and, to minimize multiple publication bias, only those without overlapping patient populations could be included in the meta-analysis, limiting the number of available studies for comparison.
The revised consensus definition of sarcopenia by the EWGSOP provides important prognostic information after elective abdominal surgery. According to this definition, sarcopenic patients were at significantly greater risk of incurring any postoperative complication, regardless of the type of elective abdominal procedure performed and despite adjusting for confounding preoperative and patient factors. Sarcopenia was also identified as an independent risk factor for poorer overall survival after elective abdominal surgery. Consensus-defined sarcopenia can be appropriately measured in the preoperative setting and early identification of sarcopenia may aid in the development of targeted exercise-based interventions aimed at minimizing sarcopenia 12,13 , which could improve outcomes for patients undergoing elective abdominal surgery. Funding B.P. is supported by the Douglas Goodfellow Medical Fellowship (Auckland Medical Research Foundation, Grafton, Auckland, New Zealand). There are no other specific grants from funding agencies in the public, commercial, or not-for-profit sectors to report relating to this manuscript.